Obesity is a condition in which body weight, especially white adipose tissue, occurs in excess, and is generally classified as having a body mass index (BMI) of ≧25 kg/m2 and as having a body fat percentage of 25% or greater for male adults and 30% or greater for female adults. Due to habits of eating high-fat diets and a lack of exercises in modern society, the percentage of people classified as obese is on the rise. According to the result of the national nutrition survey by the Ministry of Health, Labor and Welfare in 2000, the number of men who are diagnosed as obese have certainly increased during the last 10 and 20 years and about 30% of men from 40-69 years old are diagnosed as obese, and for women as well, about 30% of those 60-69 years old are diagnosed as obese.
In the past, obesity was viewed as an aesthetic problem, but today, rather than obesity per se, health impairments accompanied (or potentially accompanied) by obesity pose major clinical challenges, providing a medical grounds for the prevention and treatment of obesity. Under such circumstances, the Japan Society for the Study of Obesity (JASSO) has defined obesity as “a pathological condition that is accompanied or suspected of being accompanied by health impairments resulting from or associated with obesity and that requires medical reduction in body weight”, and proposes to deal with it as a disease entity. The health impairments as used herein include type 2 diabetes and impaired glucose tolerance as well as hypertension, hyperlipidemia, hyperuricemia, fatty liver, cardiac and cerebral vascular diseases, sleep apnea syndrome, orthopedic diseases such as osteoarthritis, menstrual disorders and the like (The Japanese Journal of Clinical Medicine (Nippon Rinsho), Supplement “Adiposis”, issued by Nippon Rinshosha Co., Ltd. on Jul. 28, 2003). As diseases resulting from obesity, malignant tumors are mentioned, and specifically, obesity has been reported to be a risk factor for the onset of breast cancer, uterine cancer, colon cancer, kidney cancer, esophageal cancer, pancreatic cancer, liver cancer, and gallbladder cancer (The Japanese Journal of Clinical Medicine (Nippon Rinsho), Supplement “Adiposis”, issued by Nippon Rinshosha Co., Ltd. on Jul. 28, 2003; Non-patent document 1, Abu-Abid et al., Journal of Medicine (USA), Jan. 1, 2002, Vol. 33, Nos. 1-4, pp. 73-86; and Nair et al., Hepatology (USA), Jul. 1, 2002, Vol. 36, No. 1, pp. 150-155). In recent years, furthermore, there has been proposed a multiple risk syndrome that increases the risk of arteriosclerotic diseases (myocardial infarction, cerebral infarction etc.) called “metabolic syndrome”, which is attracting attention since cerebral vascular diseases and cardiovascular diseases account for 30% of all deaths in Japan. Therefore, the Japan Society for the Study of Obesity, the Japan Atherosclerosis Society, the Japan Diabetes Society, the Japanese Society of Hypertension, the Japanese Circulation Society, the Japanese Society of Nephrology, the Japanese Society on Thrombosis and Hemostasis, the Japanese Society of Internal Medicine collaborated to draw up its diagnostic criteria and announced the criteria at the press conference of the Meeting of the Japanese Society of Internal Medicine on Apr. 8, 2005. According to the criteria, with visceral fat (fat accumulation in internal organs) set at the center of the criteria, men with a waist circumference of 85 cm or greater and women with a waist circumference of 90 cm or greater who have two or more risks of serum lipid abnormality (either one or both of a triglyceride value of 150 mg/dL or more and a HDL cholesterol value of 40 mg/dL or less), high blood pressure value (either one or both of a systolic pressure of 130 mmHg or more and a diastolic pressure of 85 mmHg) and high blood glucose (a fasting blood glucose level of 110 mg/dL or more) are diagnosed as having the metabolic syndrome (Journal of the Japanese Society of Internal Medicine, A research committee on the diagnostic criteria for metabolic syndrome, April, 2005 issue, Vol. 94, pp. 188-203). When this criteria was used, it is reported, among 290 male adults who were undergoing health screening, 61 people (21%) were diagnosed as obese, whereas 27 people (9%) were diagnosed as having the metabolic syndrome, and 9 people (3%) were not included in obesity but were diagnosed as having the metabolic syndrome (Igaku no Ayumi, Kazuo Takahashi and Yasushi Saito, 2005, Vol. 213, No. 6, pp. 549-554).
Since the possible cause of obesity is essentially the persistent excess of energy (calorie) taken in over energy (calorie) consumed, it is recommended that obese people or people with obesity undergo the diet therapy and/or the exercise therapy in order to lower body weight, especially body fat percentage. However, since the continuance of these therapies poses considerable stress on an enhanced appetite, adaptation to changes in life styles, and exercise tolerance, various difficulties must be overcome to continue the therapies. It is likely that when the calorie intake was decreased in the diet therapy, the so-called rebound phenomenon, i.e., that the intestinal absorption of nutrients increases and energy metabolism lowers, may occur, and therefore the continuance of the diet therapy may be abandoned. Though medical treatments of obesity include central anorectic drugs, agents promoting thermal metabolism, absorption-inhibiting agents, steatogenesis-inhibiting agents, etc., the only agent that can be used under the health insurance system in Japan at present is mazindol which is classified as a central anorexigenic drug. However, mazindol is a stimulant-like compound, and has side effects of excitation, irritation, cardiovascular load, dysuria etc., and the period of use has been limited to within 3 months, and thus it is not considered a drug that can be easily used (Novartis Pharma KK, “Sanorex 0.5 mg tablet”, package insert).
Excessive reduction in body weight (so-called “emaciation”) or food intake (so-called “anorexia”) concerning obesity is problematic since it can cause infection due to a reduced defense reaction (immunity), hematopoietic disorders, amenorrhea or irregular menstruation, infertility, mental disorders, peripheral nerve paralysis, hypotension, osteoporosis etc. Generally, when BMI is <18.5 Kg/m2, or men with a body fat percentage of 10% or less and women with a body fat percentage of 15% or less are classified as emaciated. According to the result of a national nutrition survey by the Ministry of Health, Labor and Welfare in 2000, the percentage of women with BMI of <18.5 Kg/m2 in the 20-39 year-old bracket has risen steadily in the past 10 and 20 years, and in the 20-29 year-old bracket about 24% are classified as “emaciated”. This is possibly caused by intentional reduction in food intake by young women due to excessive concern over weight. However, in anorexia nervosa (food refusal), one of the central food intake disorders prevalent among this age group, appetite per se extremely decreases and hence the nutritional condition aggravates, sometimes leading to death due to general prostration. Also, as appetite-lowering diseases that include concepts formerly called gastroptosis, gastroatonia, or neurogenic gastritis, there is a disease termed functional dyspepsia, which is said to exhibit symptoms of early satiety after meals and reduced appetite etc. (Talley et al., Gut 1999, 45, Suppl. 2:1137-42). Furthermore, as causes of anorexia, there can be mentioned cancer, inflammatory diseases, reduced function of the pituitary, the thyroid, or the adrenal etc., post-surgery, excessive stress and the like, and persistent anorexia for a long time under these conditions may cause body weakening.
Under these circumstances, in recent years, vigorous research has been under taken on biological factors that control food intake and also on the relationships of factors such as leptin, adiponectin and ghrelin on the control of food intake. At present, however, no conclusions have been made on factors that play a leading role in food intake control and/or body weight control, and no factors such as those described above have yet been used in therapies. Thus, there is a strong need for identifying factors that play a leading role in the control of food intake and/or the control of body weight and for applying them into the treatment of obesity and adipogenesis. However, few factors have been reported to be involved in food intake control and/or body weight control and for the PPARγ agonist widely used as a therapeutic agent for diabetes mellitus, no direct involvement in food intake control and/or body weight control has been reported.
On the other hand, nuclear EF-hand acidic (NEFA) is also called nucleobindin II (NUCB 2), and a polypeptide encoded by the NEFA gene has a calcium-binding domain (EF domain) and a DNA-binding domain (Biol Chem Hoppe Seyler 1994, Aug; 375(8):497-512). NEFA has a high homology with nucleobindin and is considered to be a member of the DNA-binding factor called the EF-hand superfamily having a reactivity with calcium (Karabinos et al., Mol Biol Evol 1996 September; 13(7):990-8). Though NEFA is being investigated regarding its calcium-binding ability, its binding with necdin, a cellular growth control factor, etc. (Kroll et al., Biochem. Biophys. Res. Commun. 1999, 24, pp. 1-8 and Tanimura et al., J. Biol. Chem. 2000, October 13:275(41):31674-81), there are no reports on its detailed functions. NEFA has been studied regarding the possibility of being a causative gene of Usher's syndrome, an opthalmological disease, and gastric cancer (Doucet et al., Biochim. Biophys. Acta. 1998 July 1; 1407(1):84-91 and Line et al., Br. J. Cancer 2002, June 5:86(11):1824-30). Furthermore, though the possibility of the NEFA polypeptide being extracellularly secreted has been demonstrated because it has a signal sequence at the amino terminal end (Non-patent document 5), there are no reports on the physiological or pharmacological role as a result of extracellular secretion thereof. Also, there are no reports that suggest a relationship between NEFA and food intake control and/or body weight control.